ArticleBMC developmental biology2008
Neurotransmitter alterations in embryonic succinate semialdehyde dehydrogenase (SSADH) deficiency suggest a heightened excitatory state during development.
Article in BMC developmental biology, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 40 citations in OpenAlex.
- A Randomized Controlled Trial of SGS-742, a γ-aminobutyric acid B (GABA-B) Receptor Antagonist, for Succinic Semialdehyde Dehydrogenase Deficiency.Journal of child neurology · 2021Trial
- ALDH5A1-deficient iPSC-derived excitatory and inhibitory neurons display cell type specific alterations.Neurobiology of disease · 2024Article
- Phenotypic correlates of structural and functional protein impairments resultant from ALDH5A1 variants.Human genetics · 2023Article
- Article
- Longitudinal metabolomics in dried bloodspots yields profiles informing newborn screening for succinic semialdehyde dehydrogenase deficiency.JIMD reports · 2020Article
- Post-mortem tissue analyses in a patient with succinic semialdehyde dehydrogenase deficiency (SSADHD). I. Metabolomic outcomes.Metabolic brain disease · 2020Article
- Novel mutations in two unrelated Italian patients with SSADH deficiency.Metabolic brain disease · 2019Article
- Preclinical tissue distribution and metabolic correlations of vigabatrin, an antiepileptic drug associated with potential use-limiting visual field defects.Pharmacology research & perspectives · 2019Article
- Succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism: an update on pharmacological and enzyme-replacement therapeutic strategies.Journal of inherited metabolic disease · 2018Review
- Phenotype of GABA-transaminase deficiency.Neurology · 2017Review
- Gamma-Hydroxybutyrate (GHB) Content in Hair Samples Correlates Negatively with Age in Succinic Semialdehyde Dehydrogenase Deficiency.JIMD reports · 2017Article
- mTOR inhibitors rescue premature lethality and attenuate dysregulation of GABAergic/glutamatergic transcription in murine succinate semialdehyde dehydrogenase deficiency (SSADHD), a disorder of GABA metabolism.Journal of inherited metabolic disease · 2016Article
- Correlation of blood biomarkers with age informs pathomechanisms in succinic semialdehyde dehydrogenase deficiency (SSADHD), a disorder of GABA metabolism.Journal of inherited metabolic disease · 2016Article
- Succinic semialdehyde dehydrogenase deficiency (SSADHD): Pathophysiological complexity and multifactorial trait associations in a rare monogenic disorder of GABA metabolism.Neurochemistry international · 2016Review
- Biomarkers in a Taurine Trial for Succinic Semialdehyde Dehydrogenase Deficiency.JIMD reports · 2016Article
- Novel QTL at chromosome 6p22 for alcohol consumption: Implications for the genetic liability of alcohol use disorders.American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics · 2014Article
- Quantitation of gamma-hydroxybutyric acid in dried blood spots: feasibility assessment for newborn screening of succinic semialdehyde dehydrogenase (SSADH) deficiency.Molecular genetics and metabolism · 2013Article
- Thirty years beyond discovery--clinical trials in succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism.Journal of inherited metabolic disease · 2013Review
- Differential protein profile in zebrafish (Danio rerio) brain under the joint exposure of methyl parathion and cadmium.Environmental science and pollution research international · 2012Article
- Succinic semialdehyde dehydrogenase: biochemical-molecular-clinical disease mechanisms, redox regulation, and functional significance.Antioxidants & redox signaling · 2011Review
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Authors and funding
6 authors at 3 institutions in 3 countries.
Funding
Abstract
backgroundSSADH (aldehyde dehydrogenase 5a1 (Aldh5a1); gamma-hydroxybutyric (GHB) aciduria) deficiency is a defect of GABA degradation in which the neuromodulators GABA and GHB accumulate. The human phenotype is that of nonprogressive encephalopathy with prominent bilateral discoloration of the globi pallidi and variable seizures, the latter displayed prominently in Aldh5a1-/- mice with lethal convulsions. Metabolic studies in murine neural tissue have revealed elevated GABA [and its derivatives succinate semialdehyde (SSA), homocarnosine (HC), 4,5-dihydroxyhexanoic acid (DHHA) and guanidinobutyrate (GB)] and GHB [and its analogue D-2-hydroxyglutarate (D-2-HG)] at birth. Because of early onset seizures and the neurostructural anomalies observed in patients, we examined metabolite features during Aldh5a1-/- embryo development.
methodsEmbryos were obtained from pregnant dams sacrificed at E (embryo day of life) 10-13, 14-15, 16-17, 18-19 and newborn mice. Intact embryos were extracted and metabolites quantified by isotope dilution mass spectrometry (n = 5-15 subjects, Aldh5a1+/+ and Aldh5a1-/-) for each gestational age group. Data was evaluated using the t test and one-way ANOVA with Tukey post hoc analysis. Significance was set at the 95th centile.
resultsGABA and DHHA were significantly elevated at all gestational ages in Aldh5a1-/- mice, while GB was increased only late in gestation; SSA was not elevated at any time point. GHB and D-2-HG increased in an approximately linear fashion with gestational age. Correlative studies in human amniotic fluid from SSADH-deficient pregnancies (n = 5) also revealed significantly increased GABA.
conclusionOur findings indicate early GABAergic alterations in Aldh5a1-/- mice, possibly exacerbated by other metabolites, which likely induce a heightened excitatory state that may predispose neural networks to epilepsy in these animals.
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